ALBERT

Description: Land use change as conversion pasture to forest produces several changes on hydrological cycle. In this paper we analyze the effects on stream discharge of afforestation of a small watershed devoted to pasture using the HBV hydrological model. Streamflow data obtained over the first ten years after planting were employed to evaluate the capacity of HBV model to simulate hydrological behavior of catchment after afforestation. Obtained results indicate that the estimation of streamflow was accurate as reflected by statistics (R 2  = 0.90, NSC = 0.89 and PBIAS = 0.34). Afterwards, streamflow under pasture land use (if afforestation had not occurred) was simulated using hydro-meteorological data collected during the period of study and model parameters optimized previously, together with two parameters, pcorr and cevpfo , that were adjusted for pasture conditions. HBV model results indicate that afforestation produced a water yield reduction around 2000 mm (22% of total stream discharge) during the first ten years of planting growth. The differences between forest and pasture land cover are increasing in all seasons year by year. The greatest streamflow reduction was observed in wet period (autumn and winter) with 76% of total reduction. In summer, streamflow reduction represents only 3% of total, however, represents 24.7% of discharge in this season. Streamflow reduction was related to increase of rainfall interception (mainly in wet periods) and the increase of evapotranspiration by plantation in dry periods. This article is protected by copyright. All rights reserved.

Description: Air flows from the atmosphere into an unconfined aquifer when the water table falls during pumping tests. Pumping test results in unconfined aquifers may be significantly affected by low-permeability zones (LPZs) near the initial water table position because they restrict the downward movement of air. A transient, three-dimensional (3D) air-water two-phase flow model is employed to investigate numerically the effects of local heterogeneity on pumping test results in unconfined aquifers. Two cases of local heterogeneities are considered herein: a LPZ around the pumping well and on one side of the pumping well. Results show that the drawdown with the LPZ is significantly greater than that of the homogeneous aquifer. The differences in drawdown are the most significant at intermediate times and gradually diminish at later times. The LPZ significantly reduces air flow from the atmosphere to the aquifer. The pore air velocity in the LPZ is very low. The air pressure at the observation point under the LPZ when air begins to enter is significantly lower than the air pressure of the homogeneous aquifer at the same point. After that, the air pressure increases quickly and then increases slowly. The time for the air pressure to reach the atmospheric pressure is significantly longer. This article is protected by copyright. All rights reserved.

Description: Over the last half century, since logging for timber production became intensive, Borneo has lost much of its pristine tropical forests. The long-term consequences of associated decline in precipitation are evident, and might, in turn, cause much more severe deforestation. This article is protected by copyright. All rights reserved.

Description: The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y 13 receptor (P2Y 13 -R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y 13 -R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y 13 -R. When transiently expressed, P2Y 13 -R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y 12 receptor (P2Y 12 -R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y 13 -R in the ER, suggesting a close link between ubiquitination of P2Y 13 -R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y 13 -R and P2Y 12 -R strongly restored plasma membrane expression of P2Y 13 -R, suggesting the involvement of the intra-cytoplasmic tail of P2Y 13 -R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y 13 -R in hepatocytes, and consequently stimulated P2Y 13 -R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (〉200 %) in wild-type but not in P2Y 13 -R-deficient mice, thus reinforcing the role of P2Y 13 -R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y 13 -R expression and consequently promote the overall RCT.

Description: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has dual functions mediating both apoptosis and survival of cells. This review focusses on the current regulatory factors that control TRAIL transcription. Here, we also highlight the role of distinct transcription factors that co-operate and regulate TRAIL in different pathological states. A better understanding of the molecular signalling pathways of TRAIL-induced cell death and survival in disease may lead to more sophisticated technologies for novel therapeutic targets.

Description: Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2α on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell’s armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2α is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2α kinases in their kinase domains, underlying their common role in phosphorylating eIF2α, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2α kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2α kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed.

Description: Chromosomally separated, co-expressed genes can be in spatial proximity, but there is still debate about how this nuclear organization is achieved. Proposed mechanisms include global genome organization, preferential positioning of chromosome territories, or gene–gene sharing of various nuclear bodies. To investigate this question, we selected a set of genes that were co-expressed upon differentiation of human multipotent stem cells. We applied a novel multi-dimensional analysis procedure which revealed that prior to gene expression, the relative position of these genes was conserved in nuclei. Upon stem cell differentiation and concomitant gene expression, we found that co-expressed genes were closer together. In addition, we found that genes in the same 1-μm—diameter neighborhood associated with either the same splicing speckle or to a lesser extent with the same transcription factory. Dispersal of speckles by overexpression of the serine-arginine (SR) protein kinase cdc2-like kinase Clk2 led to a significant drop in the number of genes in shared neighborhoods. We demonstrate quantitatively that the frequencies of speckle and factory sharing can be explained by assuming stochastic selection of a nuclear body within a restricted sub-volume defined by the original global gene positioning present prior to gene expression. We conclude that the spatial organization of these genes is a two-step process in which transcription-induced association with nuclear bodies enhances and refines a pre-existing global organization.

Description: Accepting the concept of standardization introduced by the standardized precipitation index (SPI), similar methodologies have been developed to construct some other standardized drought indices such as the standardized precipitation evapotranspiration index (SPEI). In this study, the authors provided deep insight into the SPEI and recognized potential deficiencies/limitations in relating to the climatic water balance it used. By coupling another well-known Palmer drought severity index (PDSI), we proposed a new standardized Palmer drought index (SPDI) through a moisture departure probabilistic approach, which allows multiscalar calculation for accurate temporal and spatial comparison of the hydro-meteorological conditions of different locations. Using datasets of monthly precipitation, temperature and soil available water capacity, the moisture deficit/surplus was calculated at multiple temporal scales and a couple of techniques were adopted to adjust corresponding time series to a generalized extreme value distribution out of several candidates. Results of the historical records (1900–2012) for diverse climates by multiple indices showed that the SPDI was highly consistent and correlated with the SPEI and self-calibrated PDSI (SC-PDSI) at most analyzed time scales. Furthermore, a simple experiment of hypothetical temperature and/or precipitation change scenarios also verified the effectiveness of this newly-derived SPDI index in response to climate change impacts. Being more robust and preferable in spatial consistency and comparability as well as combining the simplicity of calculation with sufficient accounting of the physical nature of water supply and demand relating to droughts, the SPDI is promising to serve as a competent reference and alternative for drought assessment and monitoring. This article is protected by copyright. All rights reserved.

Description: Modeled hydrologic processes are represented in a set of numerical equations, the complexity of which can be measured by the total number of variables needed. A single dominant hydrologic process could control the hydrologic response of a watershed, and so the identification of the corresponding dominant variable(s) would aid in identifying a parsimonious model and in collecting more reliable data. By accounting for both model complexity and serial correlation in the variables, a model is used to identify the dominant variables for representing watershed scale streamflow, sediment transport, and phosphorus yields. Long-term water quantity and quality data was used to show that rainfall and non-linear soil water storage were the dominant variables for weekly streamflow, suspended sediment, and particulate phosphorus. Model accuracy did not consistently improve when other statistically significant variables were included. The results suggest that improved model performance may not justify the added model complexity. As such, identification of dominant variables would be the priority for developing parsimonious hydrologic models, especially at watershed scales. This article is protected by copyright. All rights reserved.

Description: The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline.

Description: We applied graphical methods and multivariate statistics to understand impacts of an unsewered slum catchment on nutrients and hydrochemistry of groundwater in Kampala, Uganda. Data was collected from 56 springs (groundwater), 22 surface water sites and 13 rain samples. Groundwater was acidic and dominated by Na, Cl and NO 3 . These ions were strongly correlated indicating pollution originating from wastewater infiltration from on-site sanitation systems. Results also showed that rain, which was acidic, impacted on groundwater chemistry. Using Q-mode hierarchical cluster analysis, we identified three distinct water quality groups. The first group had springs dominated by Ca-Cl-NO 3 , low values of EC, pH and cations, and relatively high NO 3 values. These springs were shown to have originated from the acidic rains because their chemistry closely corresponded to ion concentrations that would occur from rainfall recharge, which was around 3.3 times concentrated by evaporation. The second group had springs dominated by Na-K-Cl-NO 3 and Ca-Cl-NO 3 , low pH but with higher values of EC, NO 3 and cations. We interpreted these as groundwater affected by both acid rain and infiltration of wastewater from urban areas. The third group had the highest EC values (average of 688 μS/cm), low pH and very high concentrations of NO 3 (average of 2.15 mmol/L) and cations. These springs were exclusively located in slum areas and we interpreted these springs as groundwater affected by infiltration of wastewater from poorly sanitized slums areas. Surface water was slightly reducing and eutrophic due to wastewater effluents, but the contribution of groundwater to nutrients in surface water was minimal because o-PO 4 was absent whereas NO 3 was lost by denitification. Our findings suggest that groundwater chemistry in the catchment is strongly influenced by anthropogenic inputs derived from nitrogen-containing rains and domestic wastewater. This article is protected by copyright. All rights reserved.

Description: We examined the water balance a forested ombrotrophic peatland and adjacent burned peatland in the boreal plain of western Canada over a three-year period. Complete combustion of foliage and fine branches dramatically increased shortwave radiation inputs to the peat surface while halting all tree transpiration at the burned site. End-of-winter snowpack was 7-25% higher at the burned site likely due to decreased ablation from the tree canopy at the unburned site. Shrub regrowth at the burned site was rapid post-fire, and shading by the shrub canopy in the burned site approached that of the unburned site within three years after fire. Site-averaged surface resistance to evaporation was not different between sites, though surface resistance in hollows was lower in the burned site. Water loss at both burned and unburned sites is largely driven by surface evaporative losses. Evaporation at the burned site marginally exceeded the sum of pre-fire transpiration and interception at the unburned site, suggesting that ET during the growing season was 2 0–40  mm greater at the the burned peatland. While the net change in water storage during the growing season was largely unchanged by fire, the lack of low-density surface peat in the burned site appears to have decreased specific yield, leading to greater water table decline at the burned site despite similar net change in storage. This article is protected by copyright. All rights reserved.

Description: The eddy covariance (EC) method was used in a 30-month study to quantify evapotranspiration (ET) and vegetation coefficient (K CW ) for a wetland on a ranch in subtropical south Florida. To evaluate the errors in ET estimates, the EC-based ET (ET C.-EC ) and the Food and Agricultural Organization (FAO) Penman-Monteith (PM) based ET (ET C.-PM ) estimates (with literature crop coefficient K C ) were compared to each other. The ET C.-EC and FAO-PM reference ET were used to develop K CW . Regression models were developed to estimate K CW using climatic and hydrologic variables. Annual and daily ET C.-EC values were 1152 mm and 3.27 mm, respectively. The FAO-PM model underestimated ET by 25% with ET C.-EC being statistically higher than ET C.-PM . The K CW varied from 0.79 (December) to 1.06 (November). The mean K CW for dry (November-April) season (0.95) was much higher than values reported for wetlands in literature, while wet (May-October) season K CW (0.97) was closer to literature values. Higher than expected K CW values during dry season were due to higher temperature, lower humidity and perennial wetland vegetation. Regression analyses showed that factors affecting the K CW were different during the dry (soil moisture, temperature, and relative humidity) and wet (net radiation, inundation, and wind speed) seasons. Separate regression models for the dry and wet seasons were developed. ET and K CW from this study, one of the first for the agricultural wetlands in subtropical environment, will help improve the ET estimates for similar wetlands. This article is protected by copyright. All rights reserved.

Description: Research on runoff processes to date has focused on the differences between the main divisions of runoff partitioning. Indeed, our major advancements in runoff theory have come with new differentiations of different forms of overland flow and subsurface stormflow. These studies of ‘how runoff processes are different’ have resulted in our current summaries of runoff regimes conceptually (e.g. the Variable Source Area (VSA) concept) and codified in our models (e.g. TOPMODEL and its derivatives). This article is protected by copyright. All rights reserved.

Description: Supraglacial channels are an important mechanism for surface water transport over the ablation zone of western Greenland. The first assessment of the spatio-temporal distribution of surface melt channels and their relationship to supraglacial lakes over the Jakobshavn Isbrae region of Western Greenland was analyzed using Landsat ETM + panchromatic images during the 2007 melt season. A total of 1188 melt channels were delineated and show an increase in the number of melt channels throughout the season, reaching a peak on August 9. Water-filled melt channels advanced to maximum elevation of 1647 m on August 9, and attained a minimum average slope of 0.009 on July 8. The ablation zone demonstrates two hydrologic modes, where crevasse and moulin terminating channels dominate at elevations 〈800 m and higher order channel networks 〉800 m. Development of higher order networks is interrupted by flow divergence due to partitioning of melt water into vertical infiltration through moulins and crevasse fields prevalent at lower elevations. Tributary and Connector networks between 800 to 1200 m in elevation are correlated with fewer lake occurrences, relatively lower surface velocities (~50 ma -1 ) and ice flow dominated by internal deformation over basal sliding. High order channels are associated with lake basins that exceed melt water storage capacity. Evolution of channel networks is coupled to changes in melt water production, runoff, and ice dynamics with implication for the englacial and subglacial environments. This article is protected by copyright. All rights reserved.

Description: This paper reviews the use of the Generalised Likelihood Uncertainty Estimation (GLUE) methodology in the 20 years since the paper by Beven and Binley (1992) in Hydrological Processes, which is now one of the most highly cited papers in hydrology. The original conception, the on-going controversy it has generated, the nature of different sources of uncertainty and the meaning of the GLUE prediction uncertainty bounds, are discussed. The hydrological, rather than statistical, arguments about the nature of model and data errors and uncertainties that are the basis for GLUE are emphasised. The application of the IHDM model to the Gwy catchment at Plynlimon presented in the original paper is revisited, using a much larger sample of models, a wider range of likelihood evaluations and new visualisation techniques. It is concluded that there are good reasons to reject this model for that data set. This is a positive result in a research environment in that it requires improved models or data to be made available. In practice, there may be ethical issues of using outputs from models for which there is evidence for model rejection in decision making. Finally some suggestions for what is needed in the next 20 years are provided. This article is protected by copyright. All rights reserved.

Description: A short-term flood inundation prediction model has been formulated based on the combination of the super-tank model, forced with downscaled rainfall from a global numerical weather prediction model, and a one-dimensional hydraulic model. Different statistical methods for downscaled rainfall have been explored, taking into account the availability of historical data. It has been found that the full implementation of a statistical downscaling model considering physically based corrections to the numerical weather prediction model output for rainfall prediction performs better compared with an altitudinal correction method. The integration of the super-tank model into the one-dimensional hydraulic model demonstrates a minimal requirement for the calibration of rainfall-runoff and flood propagation models. Updating the model with antecedent rainfall and regular forecast renewal has enhanced the model's capabilities as a result of the data assimilation processes of the runoff and numerical weather prediction models. The results show that the predicted water levels demonstrate acceptable agreement with those measured by stream gauges and comparable to those reproduced using the actual rainfall. Moreover, the predicted flood inundation depth and extent exhibit reasonably similar tendencies to those observed in the field. However, large uncertainties are observed in the prediction results in lower, flat portions of the river basin where the hydraulic conditions are not properly analysed by the one-dimensional flood propagation model. This article is protected by copyright. All rights reserved.

Description: This study aims to analyse the combined impacts of future discharges and sea levels on erosion-sedimentation potential, and its seasonal changes, in a ~43 km long coastal river reach of South-West Finland. To our knowledge, this kind of combined study has not been performed before. In addition to surveying the present erosion-sedimentation conditions, the daily erosion-sedimentation potential is simulated with a one dimensional hydrodynamic model for the 1971–2000 and 2070–2099 periods by applying four discharge scenarios. Different sea level stages are also employed in the simulations. All scenarios forecast increasing autumn and winter discharges, but diminishing summer discharges. This indicates increasing river channel erosion, particularly during winters and autumns. Although discharge changes have altogether a greater influence on erosion-sedimentation potential, the importance of sea level changes on sedimentation is noticeable in the estuary. The rising sea level scenarios increase the sedimentation potential. In total, by 2070–2099 the erosion potential may increase in most parts of the study area. This article is protected by copyright. All rights reserved.

Description: Northern peatlands are a large source of atmospheric methane (CH 4 ) and both a source and sink of atmospheric carbon dioxide (CO 2 ). The rate and temporal variability in gas exchanges with peat soils is directly related to the spatial distribution of these free-phase gases within the peat column. In this paper we present results from surface and borehole ground penetrating radar (GPR) surveys – constrained with direct soil and gas sampling – that compare the spatial distribution of gas accumulations in two raised bogs: one in Wales (UK), the other in Maine (USA). Although the two peatlands have similar average thickness, physical properties of the peat matrix differ, particularly in terms of peat type and degree of humification. We hypothesize that these variations in physical properties are responsible for the differences in gas distribution between the two peatlands characterized by: 1) gas content up to 10.8 % associated with woody peat and presence of wood layers in Caribou Bog (Maine), and 2) a more homogenous distribution with gas content up to 5.7 % at the surface (i.e. 〈 0.5 m deep) in Cors Fochno (Wales). Our results highlight the variability in biogenic gas accumulation and distribution across peatlands and suggest that the nature of the peat matrix has a key role in defining how biogenic gas accumulates within, and is released to the atmosphere from, peat soils. This article is protected by copyright. All rights reserved.

Description: The confounding effects of step change invalidate the stationarity assumption of commonly used trend analysis methods such as the Mann-Kendall test technique, so previous studies have failed to explain inconsistencies between detected trends and observed large precipitation anomalies. The objectives of this study were to: 1) formulate a trend analysis approach that considers nonstationarity due to step changes; 2) use this approach to detect trends and extreme occurrences of precipitation in a mid-latitude Eurasian steppe watershed in north China; and 3) examine how runoff responds to precipitation trends in the study watershed. Our results indicate that annual precipitation underwent a marginal step jump around 1995. The significant annual downward trend after 1994 was primarily due to a decrease in summer rainfall; other seasons exhibited no significant precipitation trends. At a monthly scale, July rainfall after 1994 exhibited a significant downward trend, whereas precipitation in other months had no trend. The percentage of wet days also underwent a step jump around 1994 following a significant decreasing trend, although the precipitation intensity exhibited neither a step change nor any significant trend. However, both low- and high-frequency precipitation events in the study watershed occurred more often after than before 1994, probably as either a result or an indicator of climate change. In response to these precipitation changes, the study watershed had distinctly different precipitation-runoff relationships for observed annual precipitations of less than 300 mm, between 300 and 400 mm, and greater than 400 mm. This article is protected by copyright. All rights reserved.

Description: Hydrological models are useful tools to analyze present and future conditions of water quantity and quality. The integrated modeling of water and nutrients needs an adequate representation of the different discharge components. In common with many lowlands, groundwater contribution to the discharge in the North German lowlands is a key factor for a reasonable representation of the water balance especially in low flow periods. Several studies revealed that the widely used SWAT model performs poorly for low flow periods. This paper deals with the extension of the groundwater module of the SWAT model to enhance low flow representation. The current two-storage concept of SWAT was further developed to a three-storage-concept. This was realized due to modification of the groundwater module by splitting the active roundwater storage into a fast and a slow contributing aquifer. The results of this study show that the groundwater module with three storages leads to good prediction of the overall discharge especially for the recession limbs and the low flow periods. The improved performance is reflected in the signature measures for the mid segment (PBIAS: −2:4% vs. −15:9%) and the low segment (PBIAS: 14:8% vs. 46:8%) of the flow duration curve. The three-storage groundwater module is more process oriented than the original version due to the introduction of a fast and a slow groundwater flow component. The three-storage version includes a modular approach, since groundwater storages can be activated or deactivated independently for subbasin and HRU level. This article is protected by copyright. All rights reserved.

Description: Various methods have been established for the purpose of identifying and characterizing protein–protein interactions (PPIs). This diverse toolbox provides researchers with options to overcome challenges specific to the nature of the proteins under investigation. Among these techniques is a category based on proximity-dependent labeling of proteins in living cells. These can be further partitioned into either hypothesis-based or unbiased screening methods, each with its own advantages and limitations. Approaches in which proteins of interest are fused to either modifying enzymes or receptor sequences allow for hypothesis-based testing of protein proximity. Protein crosslinking and BioID (proximity-dependent biotin identification) permit unbiased screening of protein proximity for a protein of interest. Here, we evaluate these approaches and their applications in living eukaryotic cells.

Description: Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans -Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.

Description: Directional cell migration is required for proper embryogenesis, immunity, and healing, and its underpinning regulatory mechanisms are often hijacked during diseases such as chronic inflammations and cancer metastasis. Studies on migratory epithelial tissues have revealed that cells can move as a collective group with shared responsibilities. First thought to be restricted to proper epithelial cell types able to maintain stable cell–cell junctions, the field of collective cell migration is now widening to include cooperative behavior of mesenchymal cells. In this review, we give an overview of the mechanisms driving collective cell migration in epithelial tissues and discuss how mesenchymal cells can cooperate to behave as a collective in the absence of bona fide cell–cell adhesions.

Description: The nucleosome remodeling and deacetylase (NuRD) complex regulates chromatin organization, gene transcription, genomic stability and developmental signaling. NuRD has a unique dual enzymatic activity, containing an ATPase and a histone deacetylase among its six core subunits. Recent studies indicate that NuRD composition and the interplay between subunits may dictate the diverse functions of the complex. In this review, we examine the structures and biological roles of the NuRD subunits and discuss new avenues of research to advance our understanding of the NuRD-mediated signaling network.

Description: In higher organisms, innate scavenging cells maintain physiologic homeostasis by removal of the billions of apoptotic cells generated on a daily basis. Apoptotic cell removal requires efficient recognition and uptake by professional and non-professional phagocytic cells, which are governed by an array of soluble and apoptotic cell-integral signals resulting in immunologically silent clearance. While apoptosis is associated with profound suppression of adaptive and innate inflammatory immunity, we have only begun to scratch the surface in understanding how immunologic tolerance to apoptotic self manifest at either the molecular or cellular level. In the last 10 years, data has emerged implicating professional phagocytes, most notably stromal macrophages and CD8α + CD103 + dendritic cells, as critical in initiation of the regulatory cascade that will ultimately lead to long-term whole-animal immune tolerance. Importantly, recent work by our lab and others has shown that alterations in apoptotic cell perception by the innate immune system either by removal of critical phagocytic sentinels in secondary lymphoid organs or blockage of immunosuppressive pathways leads to pronounced inflammation with a breakdown of tolerance towards self. This challenges the paradigm that apoptotic cells are inherently immunosuppressive, suggesting that apoptotic cell tolerance is a “context-dependent” event.

Description: Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity. They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security. Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells. To date, most research on antimicrobial peptides has focused on their activity against bacteria. Several antimicrobial peptides specifically target fungal cells and are not active against bacteria. Others with broader specificity often have different mechanisms of action against bacteria and fungi. This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi. While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell.

Description: The ecological condition and biodiversity values of floodplain wetlands are highly dependent on the hydrological connectivity of wetlands to adjacent rivers. This paper describes a method for quantifying connectivity between floodplain wetlands and the main rivers in a wet tropical catchment of northern Australia. We used a 1-D hydrodynamic model to simulate time-varying water depths across the stream network (i.e. rivers, streams and man-made drains). The timing and duration of connectivity of seven wetlands (4 natural and 3 artificial) with the two main rivers in the catchment were then calculated for different hydrological conditions. Location and areal extent of the wetlands and the stream network were identified using high resolution laser altimetry (LiDAR) and these data formed key inputs to the hydrodynamic model. The model was calibrated using measured water depths and discharges across the floodplain. An algorithm was developed to identify contiguous water bodies at daily time steps and this gave the temporal history of connection and disconnection between wetlands and the rivers. Simulation results show that connectivity of individual wetlands to both rivers varies from 26 to 365 days during an average hydrological condition. Location, especially proximity to a main river, and wetland type (natural stream or artificial drain) were identified as key factors influencing these levels of connectivity. Some natural wetlands maintain connection with the river for most or all of the year, whereas the connectivity of some artificial wetlands varies from 26 to 36 days according to their patterns of network connection to adjacent rivers – a result that has important implications for the accessibility of these types of wetland to aquatic biota. Using readily available river gauge data, we also show how connectivity modelling can be used to identify periods when connectivity has fallen below critical thresholds for fish movement. These connectivity patterns within the floodplain network are central to the setting of river flows that will meet environmental requirements for biota that use floodplain wetlands during their life history. This article is protected by copyright. All rights reserved.

Description: Pumping tests are one of the most commonly used in-situ testing techniques for assessing aquifer hydraulic properties. Numerous researches have been conducted to predict the effects of aquifer heterogeneity on the groundwater levels during pumping tests. The objectives of the present work were 1) to predict drawdown conditions and estimate aquifer properties during pumping tests undertaken in radially symmetric heterogeneous aquifers and 2) to identify a method for assessing the transmissivity field along the radial coordinate in radially symmetric and fully heterogeneous transmissivity fields. The first objective was achieved by expanding an existing analytical drawdown formulation which was valid for a radially symmetric confined aquifer with two concentric zones around the pumping well to an N concentric zone confined aquifer having a constant transmissivity value within each zone. The formulation was evaluated for aquifers with three and four concentric zones to assess the effects of the transmissivity field on the drawdown conditions. The specific conditions under which aquifer properties could be identified using traditional methods of analysis were also evaluated. The second objective was achieved by implementing the Inverse Solution Algorithm (ISA) which was developed for petroleum reservoirs to groundwater aquifer settings. The results showed that the drawdown values are influenced by a volumetric integral of a weighting function and the transmissivity field within the cone of depression. The weighting function migrates in tandem with the expanding cone of depression. The ability of the ISA to predict radially symmetric and log-normally distributed transmissivity fields was assessed against analytical and numerical benchmarks. The results of this investigation indicated that the ISA method is a viable technique for evaluating the radial transmissivity variations of heterogeneous aquifer settings. This article is protected by copyright. All rights reserved.

Description: Genome organization into linear chromosomes likely represents an important evolutionary innovation that has permitted the development of the sexual life cycle; this process has consequently advanced nuclear expansion and increased complexity of eukaryotic genomes. Chromosome linearity, however, poses a major challenge to the internal cellular machinery. The need to efficiently recognize and repair DNA double-strand breaks that occur as a consequence of DNA damage presents a constant threat to native chromosome ends known as telomeres. In this review, we present a comparative survey of various solutions to the end protection problem, maintaining an emphasis on DNA structure. This begins with telomeric structures derived from a subset of prokaryotes, mitochondria, and viruses, and will progress into the typical telomere structure exhibited by higher organisms containing TTAGG-like tandem sequences. We next examine non-canonical telomeres from Drosophila melanogaster , which comprise arrays of retrotransposons. Finally, we discuss telomeric structures in evolution and possible switches between canonical and non-canonical solutions to chromosome end protection.

Description: Stormwater management increasingly recognises the need to emulate, to the maximum extent possible, the flow regime of receiving waters in their pre-development state. Hydrological models play a central role in assessing the catchment-scale impacts of alternative stormwater management strategies. However, because of the complexity of physical processes involved in urban hydrology, particularly subsurface flows, the predictive performance of such models is often low. We investigated how the structure of hydrological models influenced the prediction of urbanisation and stormwater management impacts on baseflow. We calibrated three conceptual models of the same reference catchment and compared the modelled flow regime from different stormwater management scenarios, using each of the three model structures. Scenarios were assessed using six metrics, characterising the whole streamflow regime and in particular baseflow. While the three models of the reference catchment represented the observed hydrograph well, the most complex structure, developed using a thorough diagnostic of the catchment behaviour, better captured the change in hydrological regime during dry years. Predictions of baseflow changes due to urbanisation varied significantly according to the model structure. Similarly, the models showed distinct responses to the stormwater management scenarios applied, especially for scenarios involving infiltration of stormwater at source. Our results confirm the importance of predicting the consequences of land use changes with conceptual models that are consistent with the hydrological behaviour of the study catchment. Future work should help quantify the uncertainties due to model structure, and thus provide practical guidance to the use of catchment models for assessing stormwater management strategies. This article is protected by copyright. All rights reserved.

Description: Although fire-induced soil water repellency (SWR) and its effects on soil hydrology and geomorphology have been studied with detail, very few studies have considered the effect of rock fragments resting on the soil surface or partly embedded in soil. In this research, we have studied the effect of rock fragments on the strength and spatial distribution of fire-induced SWR at different fire severities. A fire-affected area was selected for this experiment and classified into different zones according to fire severity (unburned, low, moderate and high) and rock fragment cover (low, 〈20%, and high, 〉60%). During 7 days after fire, SWR and infiltration rates were assessed in the soil surface covered by individual rock fragments and in the midpoint between two adjacent rock fragments (with maximum spacing of 20 cm). SWR increased with fire severity. Rock fragments resting on the soil surface increased the heterogeneity of the spatial distribution of fire-induced SWR. SWR increased significantly with rock fragment cover in bare areas under moderate and high fire severity, but quantitatively important changes were only observed under high fire severity. In areas with a low rock fragment cover, water repellency from soil surfaces covered by rock fragments increased relative to bare soil surfaces, with increasing SWR. In areas with a high rock fragment cover, SWR increased significantly from non-covered to covered soil surfaces only after low-severity burning. Rock fragment cover did not affect infiltration rates, although it decreased significantly in soil surfaces after high-severity burning in areas under low and high rock fragment cover. This article is protected by copyright. All rights reserved.

Description: The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs’ secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases.

Description: In hibitor of G rowth 1 ( ING1 ) was identified and characterized as a “candidate” tumor suppressor gene in 1996. Subsequently, four more genes, also characterized as “candidate” tumor suppressor genes, were identified by homology search: ING2, ING3, ING4 , and ING5. The ING proteins are characterized by a high homology in their C-terminal domain, which contains a Nuclear Localization Sequence and a Plant HomeoDomain (PHD), which has a high affinity to Histone 3 tri-methylated on lysine 4 (H3K4Me3). The ING proteins have been involved in the control of cell growth, senescence, apoptosis, chromatin remodeling, and DNA repair. Within the ING family, ING1 and ING2 form a subgroup since they are evolutionarily and functionally close. In yeast, only one gene, Pho23, is related to ING1 and ING2 and possesses also a PHD. Recently, the ING1 and ING2 tumor suppressor status has been fully established since several studies have described the loss of ING1 and ING2 protein expression in human tumors and both ING1 and ING2 knockout mice were reported to have spontaneously developed tumors, B cell lymphomas, and soft tissue sarcomas, respectively. In this review, we will describe for the first time what is known about the ING1 and ING2 genes, proteins, their regulations in both human and mice, and their status in human tumors. Furthermore, we explore the current knowledge about identified functions involving ING1 and ING2 in tumor suppression pathways especially in the control of cell cycle and in genome stability.

Description: Extremely low water level events have frequently occurred in the middle-lower Yangtze River (MLYR) in recent years (2006–2011). Most of these drought events coincided with the initial operation of the Three Gorges Dam (TGD). The TGD was therefore the focus of controversy about the causes of the hydrological droughts of the rivers and lakes of the region. We quantified the effects of the TGD's operation on water levels from 2006 to 2011 using a newly developed hydrodynamic model. The operation of the TGD significantly exacerbated the severe hydrological droughts that occurred in late September to November due to water impoundment, but it increased water levels from April to early June in the MLYR due to the drawdown of TGD water levels. Evidence suggests that the recent extremely low water levels were mainly due to the remarkable decline in inflows to the MLYR resulting from precipitation changes and possible human activities. Nevertheless, it should be noted that the effects of the TGD on downstream rivers and lakes will be intensified in the foreseeable future. This article is protected by copyright. All rights reserved.

Description: Water availability is one of the key environmental factors that control ecosystem functions in temperate forests. Changing climate is likely to alter the ecohydrology and other ecosystem processes that affect forest structures and functions. We constructed a multi-year water budget (2004–2010) and quantified environmental controls on an evapotranspiration (ET) in a 70-year-old mixed-oak woodland forest in northwest Ohio, USA. ET was measured using the eddy-covariance (EC) technique along with precipitation (P), soil volumetric water content (VWC), and shallow groundwater table fluctuation. Three biophysical models were constructed and validated to calculate potential ET (PET) for developing predictive monthly ET models. We found that the annual variability in ET was relatively stable and ranged from 578 mm in 2009 to 670 mm in 2010. In contrast, ET/P was more variable and ranged from 0.60 in 2006 to 0.96 in 2010. Mean annual ET/PET_FAO was 0.64 while mean annual PET_FAO/P was 1.15. Annual ET/PET_FAO was relatively stable, varying from 0.60 in 2005 to 0.72 in 2004. Soil water storage and shallow groundwater recharge during the non-growing season were essential in supplying ET during the growing season when ET exceeded P. Spring leaf area index (LAI), summer photosynthetically active radiation (PAR), and autumn and winter air temperatures (T a ) were the most significant controls of monthly ET. Moreover, LAI regulated ET during the whole growing season and higher temperatures increased ET even during dry periods. Our empirical modeling showed that the interaction of LAI and PET explained 〉90% of the variability in measured ET. Altogether we found that increases in T a and shifts in P distribution are likely to impact forest hydrology by altering shallow groundwater fluctuations, soil water storage, and ET and, consequently, alter the ecosystem functions of temperate forests. This article is protected by copyright. All rights reserved.

Description: Subsurface stormflow is thought to occur mainly in humid environments with steep terrains. However in semi-arid areas, preferential flow through macropores can also result in a significant contribution of subsurface stormflow to catchment runoff for varying catchment conditions. Most hydrological models neglect this important subsurface preferential flow. Here we use the process-oriented hydrological model Hillflow-3D, which includes a macropore flow approach, to simulate rainfall-runoff in the semi-arid Parapuños catchment in Spain, where macropore flow was observed in previous research. The model was extended for this study to account for sorptivity under very dry soil conditions. The results of the model simulations with and without macropore flow are compared. Both model versions give reasonable results for average rainfall situations, although the approach with the macropore concept provides slightly better results. The model results for scenarios of extreme rainfall events (〉 13.3 mm per 30 min) however show large differences between the versions with and without macropores. These model results compared to measured rainfall-runoff data show that the model with the macropore concept is better. Our conclusion is that preferential flow is important in controlling surface runoff in case of specific, high intensity rainfall events. Therefore preferential flow processes must be included in hydrological models where we know that preferential flow occurs. Hydrological process models with a less detailed process description may fit observed average events reasonably well but can result in erroneous predictions for more extreme events. This article is protected by copyright. All rights reserved.

Description: The central route of the South-North Water Transfer Project (CTP) is designed to divert approximately 9.5 billion m 3 of water per year from the Han River, a major tributary of the Yangtze River, to the Hai River Basin in the North China. The main purpose of this study is to assess the impact of CTP on groundwater table in the Hai River basin. Our study features a large-scale distributed hydrological model that couples a physically based groundwater module (GWM), which is subbasin-based, with a conceptual surface water module (SWM), which is grid-based. There are several grids in each subbasin and water exchange among grid are considered. Our model couples SWM and GWM, and calculates human water use at the same time. The simulation results indicate that even with the water supply by CTP, the groundwater table will continue to decline in the Hai River basin. However, the CTP water can evidently reduce the decline rate, helping alleviate groundwater over-exploitation in Hai River region. This article is protected by copyright. All rights reserved.

Description: The Tyrolean Iceman, a Copper-age ice mummy, is one of the best-studied human individuals. While the genome of the Iceman has largely been decoded, tissue-specific proteomes have not yet been investigated. We studied the proteome of two distinct brain samples using gel-based and liquid chromatography–mass spectrometry-based proteomics technologies together with a multiple-databases and -search algorithms-driven data-analysis approach. Thereby, we identified a total of 502 different proteins. Of these, 41 proteins are known to be highly abundant in brain tissue and 9 are even specifically expressed in the brain. Furthermore, we found 10 proteins related to blood and coagulation. An enrichment analysis revealed a significant accumulation of proteins related to stress response and wound healing. Together with atomic force microscope scans, indicating clustered blood cells, our data reopens former discussions about a possible injury of the Iceman’s head near the site where the tissue samples have been extracted.

Description: Complexity-reduction modelling can be useful for increasing the understanding of how the climate affects basin soil moisture response upon historical times not covered by detailed hydrological data. For this purpose, here is presented and assessed an empirical regression-based model, the European Soil Moisture Empirical Downscaling (ESMED), in which different climatic variables, easily available on the web, are addressed for simplifying the inherent complexity in the long-time studies. To accommodate this simplification, the Palmer Drought Severity Index, the precipitation, the elevation and the geographical location were used as input data in the ESMED model for predicting annual soil moisture budget. The test area was a large region including central Europe and Mediterranean countries and the spatial resolution was initially set at 50 km. ESMED model calibration was made according with the soil moisture values retrieved from the Terrestrial Water Budget Data archive by selecting randomly 285 grid points (out of 2606). Once parameterized, ESMED model was performed at validation stage both spatially and temporally. The spatial validation was made for the grid points not selected in the calibration stage while the comparison with the soil moisture outputs of the GLDAS-NOAH10 simulations upon the period 1950-2010 was carried out for the temporal validation. Moreover, ESMED results were found to be in good agreement with a root-zone soil moisture product obtained from active and passive microwave sensors from various satellite missions. ESMED model was thus found to be reliable for both the temporal and spatial validation and, hence, it might represent a useful tool to characterize the long-term dynamics of soil moisture-weather interaction. This article is protected by copyright. All rights reserved.

Description: Tundra snow cover is important to monitor as it influences local, regional, and global scale surface water balance, energy fluxes, as well as ecosystem and permafrost dynamics. Observations are already showing a decrease in spring snow cover duration at high latitudes but the impact of changing winter season temperature and precipitation on variables such as snow water equivalent (SWE) is less clear. A multi-year project was initiated in 2004 with the objective to quantify tundra snow cover properties over multiple years at a scale appropriate for comparison with satellite passive microwave remote sensing data and regional climate and hydrological models. Data collected over seven late winter field campaigns (2004 to 2010) show the patterns of snow depth and SWE are strongly influenced by terrain characteristics. Despite the spatial heterogeneity of snow cover, several inter-annual consistencies were identified. A regional average density of 0.293 g/cm 3 was derived and shown to have little difference with individual site densities when deriving SWE from snow depth measurements. The inter-annual patterns of SWE show that despite variability in meteorological forcing, there were many consistent ratios between the SWE on flat tundra and the SWE on lakes, plateaus, slopes. A summary of representative inter-annual snow stratigraphy from different terrain categories is also presented. This article is protected by copyright. All rights reserved.

Description: Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways—inhibition of apoptotic signals and activation of pro-survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics.

Description: Phagocytosis mediated by the complement receptor CR3 (also known as integrin α M ß 2 or Mac-1) is regulated by the recruitment of talin to the cytoplasmic tail of the ß 2 integrin subunit. Talin recruitment to this integrin is dependent on Rap1 activation. However, the mechanism by which Rap1 regulates this event and CR3-dependent phagocytosis remains largely unknown. In the present work, we examined the role of the Rap1 effector RIAM, a talin-binding protein, in the regulation of complement-mediated phagocytosis. Using the human myeloid cell lines HL-60 and THP-1, we determined that knockdown of RIAM impaired α M ß 2 integrin affinity changes induced by stimuli fMLP and LPS. Phagocytosis of complement-opsonized RBC particles, but not of IgG-opsonized RBC particles, was impaired in RIAM knockdown cells. Rap1 activation via EPAC induced by 8-pCPT-2′-O-Me-cAMP resulted in an increase of complement-mediated phagocytosis that was abrogated by knockdown of RIAM in HL-60 and THP-1 cell lines and in macrophages derived from primary monocytes. Furthermore, recruitment of talin to ß 2 integrin during complement-mediated phagocytosis was reduced in RIAM knockdown cells. These results indicate that RIAM is a critical component of the phagocytosis machinery downstream of Rap1 and mediates its function by recruiting talin to the phagocytic complement receptors.

Description: Protein activities controlled by receptor protein tyrosine phosphatases (RPTPs) play comparably important roles in transducing cell surface signals into the cytoplasm by protein tyrosine kinases. Previous studies showed that several RPTPs are involved in neuronal generation, migration, and axon guidance in Drosophila , and the vertebrate hippocampus, retina, and developing limbs. However, whether the protein tyrosine phosphatase type O ( ptpro ), one kind of RPTP, participates in regulating vertebrate brain development is largely unknown. We isolated the zebrafish ptpro gene and found that its transcripts are primarily expressed in the embryonic and adult central nervous system. Depletion of zebrafish embryonic Ptpro by antisense morpholino oligonucleotide knockdown resulted in prominent defects in the forebrain and cerebellum, and the injected larvae died on the 4th day post-fertilization (dpf). We further investigated the function of ptpro in cerebellar development and found that the expression of ephrin - A5b ( efnA5b ), a Fgf signaling induced cerebellum patterning factor, was decreased while the expression of dusp6 , a negative-feedback gene of Fgf signaling in the midbrain-hindbrain boundary region, was notably induced in ptpro morphants. Further analyses demonstrated that cerebellar defects of ptpro morphants were partially rescued by inhibiting Fgf signaling. Moreover, Ptpro physically interacted with the Fgf receptor 1a (Fgfr1a) and dephosphorylated Fgfr1a in a dose-dependant manner. Therefore, our findings demonstrate that Ptpro activity is required for patterning the zebrafish embryonic brain. Specifically, Ptpro regulates cerebellar formation during zebrafish development through modulating Fgf signaling.

Description: The cell is a crowded volume, with estimated mean mass percentage of macromolecules and of water ranging from 7.5 to 45 and 55 to 92.5 %, respectively. However, the concentrations of macromolecules and water at the nanoscale within the various cell compartments are unknown. We recently developed a new approach, correlative cryo-analytical scanning transmission electron microscopy, for mapping the quantity of water within compartments previously shown to display GFP-tagged protein fluorescence on the same ultrathin cryosection. Using energy-dispersive X-ray spectrometry (EDXS), we then identified various elements (C, N, O, P, S, K, Cl, Mg) in these compartments and quantified them in mmol/l. Here, we used this new approach to quantify water and elements in the cytosol, mitochondria, condensed chromatin, nucleoplasm, and nucleolar components of control and stressed cancerous cells. The water content of the control cells was between 60 and 83 % (in the mitochondria and nucleolar fibrillar centers, respectively). Potassium was present at concentrations of 128–462 mmol/l in nucleolar fibrillar centers and condensed chromatin, respectively. The induction of nucleolar stress by treatment with a low dose of actinomycin-D to inhibit rRNA synthesis resulted in both an increase in water content and a decrease in the elements content in all cell compartments. We generated a nanoscale map of water and elements within the cell compartments, providing insight into their changes induced by nucleolar stress.

Description: How animals achieve their specific body size is a fundamental, but still largely unresolved, biological question. Over the past decades, studies on the insect model system have provided some important insights into the process of body size determination and highlighted the importance of insulin/insulin-like growth factor signaling. Fat body, the Drosophila counterpart of liver and adipose tissue, senses nutrient availability and controls larval growth rate by modulating peripheral insulin signaling. Similarly, insulin-like growth factor I produced from liver and muscle promotes postnatal body growth in mammals. Organismal growth is tightly coupled with the process of sexual maturation wherein the sex steroid hormone attenuates body growth. This review summarizes some important findings from Drosophila and mammalian studies that shed light on the general mechanism of animal size determination.

Description: Signal transduction pathways transduce information about the outside of the cell to the nucleus, regulating gene expression and cell fate. To reliably inform the cell about its surroundings, information transfer has to be robust against typical perturbation that a cell experiences. Robustness of several mammalian signaling pathways has been studied recently by quantitative experimentation and using mathematical modeling. Here, we review these studies, and describe the emerging concepts of robustness and the underlying mechanisms.

Description: The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.

Description: Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαβ+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function.

Description: Immunotherapy aims to re-engage and revitalize the immune system in the fight against cancer. Research over the past decades has shown that the relationship between the immune system and human cancer is complex, highly dynamic, and variable between individuals. Considering the complexity, enormous effort and costs involved in optimizing immunotherapeutic approaches, clinically applicable tools to monitor therapy-induced immune responses in vivo are most warranted. However, the development of such tools is complicated by the fact that a developing immune response encompasses several body compartments, e.g., peripheral tissues, lymph nodes, lymphatic and vascular systems, as well as the tumor site itself. Moreover, the cells that comprise the immune system are not static but constantly circulate through the vascular and lymphatic system. Molecular imaging is considered the favorite candidate to fulfill this task. The progress in imaging technologies and modalities has provided a versatile toolbox to address these issues. This review focuses on the detection of therapy-induced anticancer immune responses in vivo and provides a comprehensive overview of clinically available imaging techniques as well as perspectives on future developments. In the discussion, we will focus on issues that specifically relate to imaging of the immune system and we will discuss the strengths and limitations of the current clinical imaging techniques. The last section provides future directions that we envision to be crucial for further development.

Description: Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.

Description: Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligase-dependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review.

Description: Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis.

Description: The main objective of this paper is to provide comparative-quantitative examinations on capabilities of 2DH and pseudo-3D modelling approaches for simulating spatial and temporal variability of the flow and salinity in Lake Urmia, Iran. The water quality in the lake has been an environmentally important subject partly because this shallow hyper saline aquatic ecosystem is considered to be one of the largest natural habitats of a unique multi-cellular organism, Artemia urmiana . This brine shrimp is the major food source for many of the protected and rare shorebirds that visit the lake. Artemia urmiana can grow and survive in certain ranges of salinity and their disappearance could lead to an alteration of existing equilibria. The lake has also experienced considerable man-made changes during the past 3 decades. A newly built crossing embankment almost divided the lake into two northern and southern halves. A relatively small opening of 1.25kmin the new embankment provides water connections between the two halves. As a result, the flow and salinity regimes have been significantly changed. This might have had adverse serious impacts on the lake ecosystem. In the current study the 2DH hydrodynamic model has been found to provide reasonable predictions for the flow regime in the lake, while its salinity predictions have not been consistent with the field observations.Thepseudo-3D model has produced results fairly close to the salinity measurements and its temporal and spatial variations. The pseudo-3Dmodelhas been used for evaluating the embankment effects on the lake hydrodynamics and on the salinity conditions. The effectiveness of introducing a different number or length of openings in the embankment for restoring the pre-embankment conditions has also been examined. These remedy options have been found not to offer substantial improvements to the lake existing ecosystem. This article is protected by copyright. All rights reserved.

Description: Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH.

Description: DING proteins, named after their conserved N-terminus, form an overlooked protein family whose members were generally discovered through serendipity. It is characterized by an unusually high sequence conservation, even between distantly related species, and by an outstanding diversity of activities and ligands. They all share a demonstrated capacity to bind phosphate with high affinity or at least a predicted phosphate-binding site. However, DING protein genes are conspicuously absent from databases. The many novel family members identified in recent years have confirmed that DING proteins are ubiquitous not only in animals and plants but probably also in prokaryotes. At the functional level, there is increasing evidence that they participate in many health-related processes such as cancers as well as bacterial ( Pseudomonas ) and viral (HIV) infections, by mechanisms that are now beginning to be understood. They thus represent potent targets for the development of novel therapeutic approaches, especially against HIV. The few genomic sequences that are now available are starting to give some clues on why DING protein genes and mRNAs are well conserved and difficult to clone. This could open a new era of research, of both fundamental and applied importance.

Description: Subsurface flow and heat transport near Freienbrink, NE Germany, was simulated in order to study groundwater-surface water exchange between a floodplains aquifer and a section of the lowland River Spree and an adjacent oxbow. Groundwater exfiltration was the dominant process and only fast surface water level rises resulted in temporary infiltration into the aquifer. The main groundwater flow paths are identified based on a 3D groundwater flow model. To estimate mass fluxes across the aquifer-surface water interfaces, a 2D flow and heat transport modelling approach along a transect of 12 piezometers was performed. Results of steady-state and transient water level simulations show an overall high accuracy with a Spearman coefficient ρ = 0.9996 and RMSE = 0.008 m. Based on small groundwater flow velocities of about 10 -7 to 10 -6  ms -1 mean groundwater exfiltration rates of 233 l m -2 d -1 are calculated. Short periods of surface water infiltration into the aquifer do not exceed 10 days and the infiltration rates are in the same range. The heat transport was modelled with slightly less accuracy (ρ = 0.8359 and RMSE = 0.34 °C). In contrast to the predominant groundwater exfiltration, surface water temperatures determine the calculated temperatures in the upper aquifer below both surface water bodies down to 10 m during the whole simulation period. These findings emphasize prevailing of heat conduction over advection in the upper aquifer zones, which seems to be typical for lowland streams with sandy aquifer materials and low hydraulic gradients. Moreover, this study shows the potential of coupled numerical flow and heat transport modelling to understand groundwater-surface water exchange processes in detail. This article is protected by copyright. All rights reserved.

Description: Particles eroded from hillslopes and exported to rivers are recognized to be composite particles of high internal complexity. Their architecture and composition is known to influence their transport behaviour within the water column relative to discrete particles. To-date, hillslope erosion studies consider aggregates to be stable once they are detached from the soil matrix. However, lowland rivers and estuaries studies often suggest that particle structure and dynamics are controlled by flocculation within the water column. In order to improve the understanding of particle dynamics along the continuum from hillslopes to the lowland river environment, soil particle behaviour was tested under controlled laboratory conditions. Seven flume erosion and deposition experiments, designed to simulate a natural erosive event, and five shear cell experiments were performed using three contrasting materials: two of them were poorly developed and as such can not be considered as soils, whilst the third one was a calcareous brown soil. These experiments revealed that soil aggregates were prone to disaggregation within the water column and that flocculation may affect their size distribution during transport. Large differences in effective particle size were found between soil types during the rising limb of the bed shear stress sequence. Indeed, at the maximum applied bed shear stress, the aggregated particles median diameter was found to be three times larger for the well-developed soil than for the two others. Differences were smaller in the falling limb, suggesting that soil aggregates underwent structural changes. However, characterization of particles strength parameters showed that these changes did not fully turn soil aggregates into flocs, but rather into hybrid soil aggregate-floc particles. This article is protected by copyright. All rights reserved.

Description: Submarine groundwater discharges (SGD) were investigated in a marine watershed in south-eastern Korea using water budget analysis and a 222 Rn mass balance model. Multi-layered TOPMODEL added hydrological assumption was used to estimate groundwater components in the water budget analysis. Field observations of soil moisture, rainfall, runoff and groundwater fluctuations were used for calibration and validation of the hydrologic model. Based on observed hydrological data and terrain analyses, parameters for the hydrologic model were delineated and used to describe several hydrologic responses in the watershed. SGD estimations by 222 Rn mass balance method were also performed at Il-Gwang bay in July, 2010, and May, June, July and Nov. 2011. The estimated groundwater through hydrologic modeling and water balance analysis was 1.3x10 6  m 3 /year, which rapidly increased during typhoon season due to heavy rainfall and permeable geologic structure. The estimated groundwater was approximately 3.7-27.1 % of SGD as evaluated by 222 Rn mass balance method ranges 3.44 and 17.45 m 3  m -2  year -1 . Even though SGD is predominantly influenced by tide fluctuation, the head gradient (difference) from hydrologic processes associated with heavy rainfalls can also extra significant influences. Comprehensive understanding of SGD evaluation can be improved through a simultaneous application of both these approaches. This article is protected by copyright. All rights reserved.

Description: Fallout radionuclides 137 Cs and 210 Pb are well established as tracers of surface and sub-surface soil erosion contributing sediment to river systems. However without additional information it has not been possible to distinguish sub-surface soil erosion sources. Here we use the fallout radionuclide 7 Be (half-life 53 days) in combination with 137 Cs and excess 210 Pb to trace the form of erosion contributing sediment in large river catchments in eastern Australia; the Logan River (area 3,700 km 2 ), Bowen River (9,400 km 2 ) and Mitchell River (4,700 km 2 ). We show that the combination of 137 Cs, excess 210 Pb and 7 Be can discriminate horizontally-aligned sub-surface erosion sources (rilled and scalded hillslopes and the floors of incised drainage lines and gully ‘badland’ areas) from vertical erosion sources (channel banks and gully walls). Specifically, sub-surface sources of sediment eroded during high rainfall and high river flow events have been distinguished by the ability of rainfall-derived 7 Be to label horizontal soil surfaces, but not vertical. Our results indicate that in the two northern catchments erosion of horizontal sub-surface soil sources contributed almost as much fine river sediment as vertical channel banks, and several times the contribution of hillslope topsoils. This result improves on source discrimination provided previously and indicates that in some areas erosion of hillslope soils may contribute significantly to sediment yield, but not as topsoil loss. We find that in north-eastern Australia scalded areas on hillslopes and incising drainage lines may be sediment sources of comparable importance to vertical channel banks. Previous studies have used the combination of 137 Cs, excess 210 Pb and 7 Be to estimate soils losses at the hillslope scale. Here we show that with timely and judicious sampling of soil and sediment during and immediately after high flow events 7 Be measurements can augment fallout 137 Cs and 210 Pb to provide important erosion source information over large catchments. This article is protected by copyright. All rights reserved.

Description: Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons.

Description: The hydrology of tropical dry forests have been poorly characterised when compared to their humid temperate and wet tropical counterparts. Despite accounting for more than 42% of all tropical forests and roughly 19% of the Earth's total forest, tropical dry forest represent less than 1% of the forest hydrology literature. The need for substantial hydrological research in tropical dry forests is extremely important, given that many tropical dry forest regions are currently water stressed due to high population densities and rapid land use change. Furthermore, future climate change scenarios are expected to have significant implications for the hydrological functioning of these catchments and will likely enhance pressures on already limited water resources. This paper provides an overview on the state of hydrological knowledge, particularly runoff generation, of tropical dry forests. We further highlight the research gaps and identify research priorities for tropical dry forests, and issue a call for increased hydrological research efforts in these forests. This article is protected by copyright. All rights reserved.

Description: Mechanical forces are increasingly recognized as central factors in the regulation of tissue morphogenesis and homeostasis. Central to the transduction of mechanical information into biochemical signaling is the contractile actomyosin cytoskeleton. Fluctuations in actomyosin contraction are sensed by tension sensitive systems at the interface between actomyosin and cell adhesion complexes. We review the current knowledge about the mechanical coupling of cell–cell junctions to the cytoskeleton and highlight the central role of α-catenin in this linkage. We assemble current knowledge about α-catenin’s regulation by tension and about its interactions with a diversity of proteins. We present a model in which α-catenin is a force-regulated platform for a machinery of proteins that orchestrates local cortical remodeling in response to force. Finally, we highlight recently described fundamental processes in tissue morphogenesis and argue where and how this α-catenin-dependent cadherin mechanotransduction may be involved.

Description: Like most positive-strand RNA viruses, hepatitis C virus (HCV) forms a membrane-associated replication complex consisting of replicating RNA, viral and host proteins anchored to altered cell membranes. We used a combination of qualitative and quantitative electron microscopy (EM), immuno-EM, and the 3D reconstruction of serial EM sections to analyze the host cell membrane alterations induced by HCV. Three different types of membrane alteration were observed: vesicles in clusters (ViCs), contiguous vesicles (CVs), and double-membrane vesicles (DMVs). The main ultrastructural change observed early in infection was the formation of a network of CVs surrounding the lipid droplets. Later stages in the infectious cycle were characterized by a large increase in the number of DMVs, which may be derived from the CVs. These DMVs are thought to constitute the membranous structures harboring the viral replication complexes in which viral replication is firmly and permanently established and to protect the virus against double-stranded RNA-triggered host antiviral responses.

Description: Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.

Description: Bone-tissue engineering is a therapeutic target in the field of dental implant and orthopedic surgery. It is therefore essential to find a microenvironment that enhances the growth and differentiation of osteoblasts both from mesenchymal stem cells (MSCs) and those derived from dental pulp. The aim of this review is to determine the relationship among the proteins fibronectin (FN), osteopontin (OPN), tenascin (TN), bone sialoprotein (BSP), and bone morphogenetic protein (BMP2) and their ability to coat different types of biomaterials and surfaces to enhance osteoblast differentiation. Pre-treatment of biomaterials with FN during the initial phase of osteogenic differentiation on all types of surfaces, including slotted titanium and polymers, provides an ideal microenvironment that enhances adhesion, morphology, and proliferation of pluripotent and multipotent cells. Likewise, in the second stage of differentiation, surface coating with BMP2 decreases the diameter and the pore size of the scaffold, causing better adhesion and reduced proliferation of BMP-MSCs. Coating oligomerization surfaces with OPN and BSP promotes cell adhesion, but it is clear that the polymeric coating material BSP alone is insufficient to induce priming of MSCs and functional osteoblastic differentiation in vivo. Finally, TN is involved in mineralization and can accelerate new bone formation in a multicellular environment but has no effect on the initial stage of osteogenesis.

Description: Since their description in the late 1990s, human artificial chromosomes (HACs) carrying a functional kinetochore were considered as a promising system for gene delivery and expression with a potential to overcome many problems caused by the use of viral-based gene transfer systems. Indeed, HACs avoid the limited cloning capacity, lack of copy number control and insertional mutagenesis due to integration into host chromosomes that plague viral vectors. Nevertheless, until recently, HACs have not been widely recognized because of uncertainties of their structure and the absence of a unique gene acceptor site. The situation changed a few years ago after engineering of HACs with a single loxP gene adopter site and a defined structure. In this review, we summarize recent progress made in HAC technology and concentrate on details of two of the most advanced HACs, 21HAC generated by truncation of human chromosome 21 and alphoid tetO -HAC generated de novo using a synthetic tetO-alphoid DNA array. Multiple potential applications of the HAC vectors are discussed, specifically the unique features of two of the most advanced HAC cloning systems.

Description: The M-type kinesin isoform, Kif9, has recently been implicated in maintaining a physical connection between the centrosome and nucleus in Dictyostelium discoideum. However, the mechanism by which Kif9 functions to link these two organelles remains obscure. Here we demonstrate that the Kif9 protein is localized to the nuclear envelope and is concentrated in the region underlying the centrosome point of attachment. Nuclear anchorage appears mediated through a specialized transmembrane domain located in the carboxyl terminus. Kif9 interacts with microtubules in in vitro binding assays and effects an endwise depolymerization of the polymer. These results suggest a model whereby Kif9 is anchored to the nucleus and generates a pulling force that reels the centrosome up against the nucleus. This is a novel activity for a kinesin motor, one important for progression of cells into mitosis and to ensure centrosome-nuclear parity in a multinuclear environment.

Description: Anti-apoptotic Bcl-2-family members not only neutralize pro-apoptotic proteins but also directly regulate intracellular Ca 2+ signaling from the endoplasmic reticulum (ER), critically controlling cellular health, survival, and death initiation. Furthermore, distinct Bcl-2-family members may selectively regulate inositol 1,4,5-trisphosphate receptor (IP 3 R): Bcl-2 likely acts as an endogenous inhibitor of the IP 3 R, preventing pro-apoptotic Ca 2+ transients, while Bcl-X L likely acts as an endogenous IP 3 R-sensitizing protein promoting pro-survival Ca 2+ oscillations. Furthermore, distinct functional domains in Bcl-2 and Bcl-X L may underlie the divergence in IP 3 R regulation. The Bcl-2 homology (BH) 4 domain, which targets the central modulatory domain of the IP 3 R, is likely to be Bcl-2’s determining factor. In contrast, the hydrophobic cleft targets the C-terminal Ca 2+ -channel tail and might be more crucial for Bcl-X L ’s function. Furthermore, one amino acid critically different in the sequence of Bcl-2’s and Bcl-X L ’s BH4 domains underpins their selective effect on Ca 2+ signaling and distinct biological properties of Bcl-2 versus Bcl-X L . This difference is evolutionary conserved across five classes of vertebrates and may represent a fundamental divergence in their biological function. Moreover, these insights open novel avenues to selectively suppress malignant Bcl-2 function in cancer cells by targeting its BH4 domain, while maintaining essential Bcl-X L functions in normal cells. Thus, IP 3 R-derived molecules that mimic the BH4 domain’s binding site on the IP 3 R may function synergistically with BH3-mimetic molecules selectivity suppressing Bcl-2’s proto-oncogenic activity. Finally, a more general role for the BH4 domain on IP 3 Rs, rather than solely anti-apoptotic, may not be excluded as part of a complex network of molecular interactions.

Description: Bone is a dynamic tissue that depends on the intricate relationship between protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) for maintaining homeostasis. PTKs and PTPs act like molecular on and off switches and help modulate differentiation and the attachment of osteoclasts to bone matrix regulating bone resorption. The protein T cell ubiquitin ligand-2 (TULA-2), which is abundantly expressed in osteoclasts, is a novel histidine phosphatase. Our results show that of the two family members, only TULA-2 is expressed in osteoclasts and that its expression is sustained throughout the course of osteoclast differentiation, suggesting that TULA-2 may play a role during early as well late stages of osteoclast differentiation. Skeletal analysis of mice that do not express TULA or TULA-2 proteins (DKO mice) revealed that there was a decrease in bone volume due to increased osteoclast numbers and function. Furthermore, in vitro experiments indicated that bone marrow precursor cells from DKO mice have an increased potential to form osteoclasts. At the molecular level, the absence of TULA-2 in osteoclasts results in increased Syk phosphorylation at the Y352 and Y525/526 residues and activation of phospholipase C gamma 2 (PLCγ2) upon engagement of immune-receptor-tyrosine-based-activation-motif (ITAM)—mediated signaling. Furthermore, expression of a phosphatase-dead TULA-2 leads to increased osteoclast function. Taken together, these results suggest that TULA-2 negatively regulates osteoclast differentiation and function.

Description: In cardiac muscle, the sarcolemmal sodium/potassium ATPase is the principal quantitative means of active transport at the myocyte cell surface, and its activity is essential for maintaining the trans-sarcolemmal sodium gradient that drives ion exchange and transport processes that are critical for cardiac function. The 72-residue phosphoprotein phospholemman regulates the sodium pump in the heart: unphosphorylated phospholemman inhibits the pump, and phospholemman phosphorylation increases pump activity. Phospholemman is subject to a remarkable plethora of post-translational modifications for such a small protein: the combination of three phosphorylation sites, two palmitoylation sites, and one glutathionylation site means that phospholemman integrates multiple signaling events to control the cardiac sodium pump. Since misregulation of cytosolic sodium contributes to contractile and metabolic dysfunction during cardiac failure, a complete understanding of the mechanisms that control the cardiac sodium pump is vital. This review explores our current understanding of these mechanisms.

Description: Inteins catalyze a post-translational modification known as protein splicing, where the intein removes itself from a precursor protein and concomitantly ligates the flanking protein sequences with a peptide bond. Over the past two decades, inteins have risen from a peculiarity to a rich source of applications in biotechnology, biomedicine, and protein chemistry. In this review, we focus on developments of intein-related research spanning the last 5 years, including the three different splicing mechanisms and their molecular underpinnings, the directed evolution of inteins towards improved splicing in exogenous protein contexts, as well as novel applications of inteins for cell biology and protein engineering, which were made possible by a clearer understanding of the protein splicing mechanism.

Description: Peroxisomes constitute a dynamic compartment of almost all eukaryotic cells. Depending on environmental changes and cellular demands peroxisomes can acquire diverse metabolic roles. The compartmentalization of peroxisomal matrix enzymes is a prerequisite to carry out their physiologic function. The matrix proteins are synthesized on free ribosomes in the cytosol and are ferried to the peroxisomal membrane by specific soluble receptors. Subsequent to cargo release into the peroxisomal matrix, the receptors are exported back to the cytosol to facilitate further rounds of matrix protein import. This dislocation step is accomplished by a remarkable machinery, which comprises enzymes required for the ubiquitination as well as the ATP-dependent extraction of the receptor from the membrane. Interestingly, receptor ubiquitination and dislocation are the only known energy-dependent steps in the peroxisomal matrix protein import process. The current view is that the export machinery of the receptors might function as molecular motor not only in the dislocation of the receptors but also in the import step of peroxisomal matrix protein by coupling ATP-dependent removal of the peroxisomal import receptor with cargo translocation into the organelle. In this review we will focus on the architecture and function of the peroxisomal receptor export machinery, the peroxisomal exportomer.

Description: Drosophila possesses the core gene silencing machinery but, like all insects, lacks the canonical RNA-dependent RNA polymerases (RdRps) that in C. elegans either trigger or enhance two major small RNA-dependent gene silencing pathways. Introduction of two different nematode RdRps into Drosophila showed them to be functional, resulting in differing silencing activities. While RRF-1 enhanced transitive dsRNA-dependent silencing, EGO-1 triggered dsRNA-independent silencing, specifically of transgenes. The strain w ; da - Gal4 ; UAST - ego - 1 , constitutively expressing ego - 1 , is capable of silencing transgene including dsRNA hairpin upon a single cross, which created a powerful tool for research in Drosophila . In C. elegans , EGO-1 is involved in transcriptional gene silencing (TGS) of chromosome regions that are unpaired during meiosis. There was no opportunity for meiotic interactions involving EGO-1 in Drosophila that would explain the observed transgene silencing. Transgene DNA is, however, unpaired during the pairing of chromosomes in embryonic mitosis that is an unusual characteristic of Diptera, suggesting that in Drosophila , EGO-1 triggers transcriptional silencing of unpaired DNA during embryonic mitosis.

Description: The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.

Description: Chromosomal translocations are characteristic features of many cancers, especially lymphoma and leukemia. However, recent reports suggest that many chromosomal translocations can be found in healthy individuals, although the significance of this observation is still not clear. In this review, we summarize recent studies on chromosomal translocations in healthy individuals carried out in different geographical areas of the world and discuss the relevance of the observation with respect to oncogenesis.

Description: Microtubules are known to drive chromosome movements and to induce nuclear envelope breakdown during mitosis and meiosis. Here we show that microtubules can enforce nuclear envelope folding and alter the levels of nuclear envelope-associated heterochromatin during interphase, when the nuclear envelope is intact. Microtubule reassembly, after chemically induced depolymerization led to folding of the nuclear envelope and to a transient accumulation of condensed chromatin at the site nearest the microtubule organizing center (MTOC). This microtubule-dependent chromatin accumulation next to the MTOC is dependent on the composition of the nuclear lamina and the activity of the dynein motor protein. We suggest that forces originating from simultaneous polymerization of microtubule fibers deform the nuclear membrane and the underlying lamina. Whereas dynein motor complexes localized to the nuclear envelope that slide along the microtubules transfer forces and/or signals into the nucleus to induce chromatin reorganization and accumulation at the nuclear membrane folds. Thus, our study identified a molecular mechanism by which mechanical forces generated in the cytoplasm reshape the nuclear envelope, alter the intranuclear organization of chromatin, and affect the architecture of the interphase nucleus.

Description: Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases.

Description: Astrocytes interact with neurons and endothelial cells and may mediate exchange of metabolites between capillaries and nerve terminals. In the present study, we investigated intracellular glucose diffusion in purified astrocytes after local glucose uptake. We used a fluorescence resonance energy transfer (FRET)-based nano sensor to monitor the time dependence of the intracellular glucose concentration at specific positions within the cell. We observed a delay in onset and kinetics in regions away from the glucose uptake compared with the region where we locally super-fused astrocytes with the d -glucose-rich solution. We propose a mathematical model of glucose diffusion in astrocytes. The analysis showed that after gradual uptake of glucose, the locally increased intracellular glucose concentration is rapidly spread throughout the cytosol with an apparent diffusion coefficient ( D app ) of (2.38 ± 0.41) × 10 −10  m 2  s −1 (at 22–24 °C). Considering that the diffusion coefficient of d -glucose in water is D  = 6.7 × 10 −10  m 2  s −1 (at 24 °C), D app determined in astrocytes indicates that the cytosolic tortuosity, which hinders glucose molecules, is approximately three times higher than in aqueous solution. We conclude that the value of D app for glucose measured in purified rat astrocytes is consistent with the view that cytosolic diffusion may allow glucose and glucose metabolites to traverse from the endothelial cells at the blood–brain barrier to neurons and neighboring astrocytes.

Description: Pentameric ligand-gated ion channel (pLGIC) receptors exhibit desensitization, the progressive reduction in ionic flux in the prolonged presence of agonist. Despite its pathophysiological importance and the fact that it was first described over half a century ago, surprisingly little is known about the structural basis of desensitization in this receptor family. Here, we explain how desensitization is defined using functional criteria. We then review recent progress into reconciling the structural and functional basis of this phenomenon. The extracellular–transmembrane domain interface is a key locus. Activation is well known to involve conformational changes at this interface, and several lines of evidence suggest that desensitization involves a distinct conformational change here that is incompatible with activation. However, major questions remain unresolved, including the structural basis of the desensitization-induced agonist affinity increase and the mechanism of pore closure during desensitization.

Description: This review is designed to provide an overview of the current literature concerning vascular endothelial growth factor signaling (VEGF) in acute myeloid leukemia (AML). Aberrant VEGF signaling operates in the bone marrow of AML patients and is related to a poor prognosis. The altered signaling pathway demonstrated to interfere in several autocrine and paracrine signaling pathways. VEGF signaling promotes autocrine AML blast cell proliferation, survival, and chemotherapy resistance. In addition, VEGF signaling can mediate paracrine vascular endothelial cell-controlled angiogenesis in AML. Both effects presumably explain the association of high VEGF levels and poor therapeutic outcome. More recently, researches focusing on bone marrow stem cell niches demonstrate a role for VEGF signaling in the preservation of several cell types within these niches. The bone marrow niches are proposed to be a protective microenvironment for AML cells that could be responsible for relapses in AML patients. This implies the need of sophisticated VEGF-targeted therapeutics in AML therapy strategies. This review highlights our current understanding of aberrant VEGF signaling in AML, appoints the interference of VEGF signaling in the AML-associated microenvironment, and reflects the novelty of current VEGF-targeted therapeutics used in clinical trails for the treatment of AML.

Description: We use two hydrological models of varying complexity to study the Juncal River Basin in the Central Andes of Chile with the aim to understand the degree of conceptualization and the spatial structure that are needed to model present and future streamflow. We use a conceptual semi-distributed model based on elevation bands (WEAP), frequently used for water management, and a physically oriented, fully-distributed model (TOPKAPI-ETH) developed for research purposes mainly. We evaluate the ability of the two models to reproduce the key hydrological processes in the basin with emphasis on snow accumulation and melt, streamflow and the relationships between internal processes. Both models are capable of reproducing observed runoff and the evolution of MODIS snow cover adequately. In spite of WEAP's simple and conceptual approach for modeling snowmelt, its lack of glacier representation and snow gravitational redistribution as well as a proper routing algorithm, this model can reproduce historical data with similar goodness-of-fit as the more complex TOPKAPI-ETH. We show that the performance of both models can be improved by using measured precipitation gradients of higher temporal resolution. In contrast to the good performance of the conceptual model for the present climate, however, we demonstrate that the simplifications in WEAP lead to error compensation which results in different predictions in simulated melt and runoff for a potentially warmer future climate. TOPKAPI-ETH, using a more physical representation of processes, depends less on calibration and thus is less subject to a compensation of errors through different model components. Our results show that data obtained locally in ad-hoc short-term field campaigns are needed to complement data extrapolated from long-term records for simulating changes in the water cycle of high elevation catchments, but that these data can only be efficiently used by a model applying a spatially distributed physical representation of hydrological processes. This article is protected by copyright. All rights reserved.

Description: Land use/cover (LULC) and climate change are two main factors affecting watershed hydrology. In this paper, individual and combined impacts of LULC and climate change on hydrologic processes were analyzed applying the model Soil and Water Assessment Tool (SWAT) in a coastal Alabama watershed in USA. Temporally and spatially downscaled Global Circulation Model (GCM) outputs predict a slight increase in precipitation in the study area, which is also projected to experience substantial urban growth in the future. Changes in flow frequency and volume in the 2030s (2016–2040) compared to a baseline period (1984–2008) at daily, monthly and annual time scales were explored. A redistribution of daily streamflow is projected when either climate or LULC change was considered. High flows are predicted to increase, while low flows are expected to decrease. Combined change effect results in a more noticeable and uneven distribution of daily streamflow. Monthly average streamflow and surface runoff are projected to increase in spring and winter, but especially in fall. LULC change does not have a significant effect on monthly average streamflow, but the change affects partitioning of streamflow, causing higher surface runoff and lower baseflow. The combined effect leads to a dramatic increase in monthly average streamflow with a stronger increasing trend in surface runoff and decreasing trend in baseflow. This article is protected by copyright. All rights reserved.

Description: The fresh groundwater lenses (FGLs) of small islands can be highly vulnerable to climate change impacts, including sea-level rise (SLR). Many real cases of atoll or sandy islands involve two-layer hydrogeological conceptualizations. In this paper, the influential factors that effect FGL in two-layer small islands subject to SLR are investigated. An analytical solution describing FGLs in circular islands, composed of two geological layers, is developed for the simplified case of steady-state and sharp-interface conditions. An application of the developed model is demonstrated to estimate the FGL thickness of some real-world islands by comparison with existing FGL thickness data. Furthermore, numerical modeling is applied to extend the analysis to consider dispersion effects and to confirm comparable results for both cases. Sensitivity analyses are used to assess the importance of land-surface inundation (LSI) caused by SLR, relative to other parameters (i.e. thickness of aquifer layers, hydraulic conductivity, recharge rate, and land-surface slope) that influence the FGL. Dimensionless parameters are used to generalize the findings. The results demonstrate that LSI has a considerable impact on a FGL influenced by SLR, as expected, although the FGL volume is more sensitive to recharge, aquifer thickness and hydraulic conductivity than SLR impacts, considering typical parameter ranges. The methodology presented in this study provides water resource managers with a rapid-assessment tool for evaluating the likely impacts of SLR and accompanying LSI on FGLs. This article is protected by copyright. All rights reserved.

Description: Signaling bias refers to G protein-coupled receptor ligand ability to preferentially activate one type of signal over another. Bias to evoke signaling as opposed to sequestration has been proposed as a predictor of opioid ligand potential for generating tolerance. Here we measured whether delta opioid receptor agonists preferentially inhibited cyclase activity over internalization in HEK cells. Efficacy ( τ ) and affinity (KA) values were estimated from functional data and bias was calculated from efficiency coefficients (log τ /KA). This approach better represented the data as compared to alternative methods that estimate bias exclusively from τ values. Log ( τ /KA) coefficients indicated that SNC-80 and UFP-512 promoted cyclase inhibition more efficiently than DOR internalization as compared to DPDPE (bias factor for SNC-80: 50 and for UFP-512: 132). Molecular determinants of internalization were different in HEK293 cells and neurons with βarrs contributing to internalization in both cell types, while PKC and GRK2 activities were only involved in neurons. Rank orders of ligand ability to engage different internalization mechanisms in neurons were compared to rank order of E max values for cyclase assays in HEK cells. Comparison revealed a significant reversal in rank order for cyclase E max values and βarr-dependent internalization in neurons, indicating that these responses were ligand-specific. Despite this evidence, and because kinases involved in internalization were not the same across cellular backgrounds, it is not possible to assert if the magnitude and nature of bias revealed by rank orders of maximal responses is the same as the one measured in HEK cells.

Description: The regulation of the protein synthesis has a crucial role in governing the eukaryotic cell growth. Subtle changes of proteins involved in the translation process may alter the rate of the protein synthesis and modify the cell fate by shifting the balance from normal status into a tumoral or apoptotic one. The largest eukaryotic initiation factor involved in translation regulation is eIF3. Amongst the 13 factors constituting eIF3, the f subunit finely regulates this balance in a cell-type-specific manner. Loss of this factor causes malignancy in several cells, and atrophy in normal muscle cells. The intracellular interacting partners which influence its physiological significance in both cancer and muscle cells are detailed in this review. By delineating the global interaction network of this factor and by clarifying its intracellular role, it becomes apparent that the f subunit represents a promising candidate molecule to use for biotherapeutic applications.

Description: It is now widely accepted that neurogenesis continues throughout life. Accumulating evidence suggests that neurotransmitters are essential signaling molecules that control the different steps of neurogenesis. Nevertheless, we are only beginning to understand the precise role of neurotransmitter receptors and in particular excitatory glutamatergic transmission in the differentiation of adult-born neurons. Recent technical advances allow single-cell gene deletion to study cell-autonomous effects during the maturation of adult-born neurons. Single-cell gene deletion overcomes some of the difficulties in interpreting global gene deletion effects on entire brain areas or systemic pharmacological approaches that might result in compensatory circuit effects. The aim of this review is to summarize recent advances in the understanding of the role of NMDA receptors (NMDARs) during the differentiation of adult-born neurons and put them in perspective with previous findings on cortical development.

Description: The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development. The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided. Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators. These regulators may serve as biomarkers for predicting metastasis. Over the past few years, numerous regulators have been found correlating with metastasis. In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin–catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers. We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.

Description: Pest insect species are a burden to humans as they destroy crops and serve as vectors for a wide range of diseases including malaria and dengue. Chemical insecticides are currently the dominant approach for combating these pests. However, the de-registration of key classes of chemical insecticides due to their perceived ecological and human health risks in combination with the development of insecticide resistance in many pest insect populations has created an urgent need for improved methods of insect pest control. The venoms of arthropod predators such as spiders and scorpions are a promising source of novel insecticidal peptides that often have different modes of action to extant chemical insecticides. These peptides have been optimized via a prey–predator arms race spanning hundreds of millions of years to target specific types of insect ion channels and receptors. Here we review the current literature on insecticidal venom peptides, with a particular focus on their structural and pharmacological diversity, and discuss their potential for deployment as insecticides.

Description: MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes.

Description: Blastomere biopsy is used in preimplantation genetic diagnosis; however, the long-term implications on the offspring are poorly characterized. We previously reported a high risk of memory defects in adult biopsied mice. Here, we assessed nervous function of aged biopsied mice and further investigated the mechanism of neural impairment after biopsy. We found that aged biopsied mice had poorer spatial learning ability, increased neuron degeneration, and altered expression of proteins involved in neural degeneration or dysfunction in the brain compared to aged control mice. Furthermore, the MeDIP assay indicated a genome-wide low methylation in the brains of adult biopsied mice when compared to the controls, and most of the genes containing differentially methylated loci in promoter regions were associated with neural disorders. When we further compared the genomic DNA methylation profiles of 7.5-days postconception (dpc) embryos between the biopsy and control group, we found the whole g e nome low methylation in the biopsied group, suggesting that blastomere biopsy was an obstacle to de novo methylation during early embryo development. Further analysis on mRNA profiles of 4.5-dpc embryos indicated that reduced expression of de novo methylation genes in biopsied embryos may impact de novo methylation. In conclusion, we demonstrate an abnormal neural development and function in mice generated after blastomere biopsy. The impaired epigenetic reprogramming during early embryo development may be the latent mechanism contributing to the impairment of the nervous system in the biopsied mice, which results in a hypomethylation status in their brains.

Description: Mapping groundwater discharge zones at broad spatial scales remains a challenge, particularly in data sparse regions. We applied a regional scale mapping approach based on thermal remote sensing to map discharge zones in a complex watershed with a broad diversity of geological materials, land cover and topographic variation situated within the Prairie Parkland of northern Alberta, Canada. We acquired winter thermal imagery from the USGS Landsat archive to demonstrate the utility of this data source for applications that can complement both scientific and management programs. We showed that the thermally determined potential discharge areas were corroborated with hydrological (spring locations) and chemical (conservative tracers of groundwater) data. This study demonstrates how thermal remote sensing can form part of a comprehensive mapping framework to investigate groundwater resources over broad spatial scales. This article is protected by copyright. All rights reserved.

Description: The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such gas that can be sensed by both prokaryotic and eukaryotic cells and in response to altered levels, elicit the activation of multiple adaptive pathways. The outcomes of activating CO 2 -sensitive pathways in various species include increased virulence of fungal and bacterial pathogens, prey-seeking behavior in insects as well as taste perception, lung function, and the control of immunity in mammals. In this review, we discuss what is known about the mechanisms underpinning CO 2 sensing across a range of species and consider the implications of this for physiology, disease progression, and the possibility of developing new therapeutics for inflammatory and infectious disease.

Description: The blood–brain barrier (BBB) is a dynamic structure that maintains the homeostasis of the brain and thus proper neurological functions. BBB compromise has been found in many pathological conditions, including neuroinflammation. Monocyte chemoattractant protein-1 (MCP1), a chemokine that is transiently and significantly up-regulated during inflammation, is able to disrupt the integrity of BBB and modulate the progression of various diseases, including excitotoxic injury and hemorrhage. In this review, we first introduce the biochemistry and biology of MCP1, and then summarize the effects of MCP1 on BBB integrity as well as individual BBB components.